All ETDs from UAB

Advisory Committee Chair

Laurie E Harrington

Advisory Committee Members

Charles O Elson

Jeffrey Engler

Robin G Lorenz

Chander Raman

Casey T Weaver

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The intestinal environment is extremely complex due to the dynamic interactions between host cells and luminal contents. The immune cells located in the intestine are responsible for sensing and responding to intestinal pathogens as well as maintaining tolerance to non-pathogenic organisms and environmental antigens. Disruption in this delicate balance results in chronic intestinal inflammation. Particularly important to the maintenance of intestinal homeostasis are CD4 T cells and innate lymphoid cells (ILCs). These cells produce cytokines in an antigen-specific and antigen-independent manner, respectively, and have analogous subsets with similar cytokine profiles. CD4 T cells and ILCs expressing ROR gamma t (Th17 cells and group 3 ILCs, respectively) are predominantly located in the intestine where they function in both protective and pathologic capacities. The precise mechanisms by which these cells are regulated in the intestine have yet to be fully elucidated. Previous studies have shown that the Th17-associated cytokine interleukin-21 (IL-21) acts to induce Th17 cells and suppress regulatory T (Treg) cells, thereby controlling the balance between pro- and anti-inflammatory T cells, but its role in the intestine is unknown. Here we show that CD4 T cell-derived IL-21 does not impact the generation of Th17 or Treg cells in the intestine during homeostasis or chronic inflammation, but does contribute to intestinal inflammation. We also demonstrate that autocrine IL-21 signaling is not critical for the induction of colitis, implying that IL-21 promotes inflammation via a mechanism independent of CD4 T cells. In addition, we show that IL-21 also acts on ILC3s by inducing IL-22 production while suppressing IL-17A production, imparting a phenotype that has been shown to be protective against intestinal inflammation. In line with this, we establish that expression of IL-21R on innate cells is protective in a CD4 T cell-driven model of colitis, emphasizing the effect of IL-21 on ILC3s. Collectively, our data reveal both pathogenic and protective roles for IL-21 in the intestine and bring to light a novel mechanism for the regulation of ILCs by CD4 T cells.

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